Project 1 will evaluate the role of corticolimbic circuitry in extinction training and cue- and methamphetamine-induced reinstatement of drug-seeking in animals trained to self-administer methamphetamine using both a short and long access treatment protocol. It is hypothesized that the cognitive impairment that has been well documented in methamphetamine addicts will be manifested in this rat model as deficits in extinction training. Further, poor extinction learning in animals trained on a long access methamphetamine protocol will arise from the fact that the prefrontal cortex, which is normally engaged by extinction training, is impaired and therefore no longer able to regulate the reinstatement of drug-seeking. Thus, the lack of prefrontal involvement is hypothesized to exacerbate reinstatement responding to both a previously associated Pavlovian conditioned cue and a noncontingent injection of methamphetamine. This basic protocol for methamphetamine self-administration, extinction and reinstatement will be developed in collaboration with Project 3 that will use this protocol to examine cognitive effects of methamphetamine self-administration. Also, circuitry maps generated in Project 1 will be integrated with neuroimaging data obtained from methamphetamine addicts in Project 2 who will undergo analogous procedure of cue-induced drug interest and subsequent extinction of the cue-induced response. Finally, Projects 3 and 4 will examine the effects of putative cognitive enhancers, Nacetylcysteine, D-cycloserine and modafinil in both the animal model of methamphetamine extinction and reinstatement and in methamphetamine addicts. Positive effects in projects 3 or 4 will then be integrated with the present project to determine where in the brain these drugs may be ameliorating addiction-related behaviors. Based upon the hypothesis that methamphetamine-induced deficits in prefrontal cortical function inhibit extinction learning and exacerbate the reinstatement of drug-seeking, it is anticipated that any effect of systemic treatment with cognitive enhancers identified in Projects 3 or 4 will be replicated by microinjecting the drug directly into the prefrontal cortex. By identifying sites of action in the brain by drugs capable of ameliorating methamphetamine addiction, future proteomic and in vivo multiphoton neuroimaging can be more efficiently targeted to sites of drug action within the brain, and to identify new cellular targets for future improvements in pharmacotherapies for methamphetamine addicts.